The genetic landscape and clinical implication of pediatric Moyamoya angiopathy in an international cohort

Abstract

Pediatric Moyamoya Angiopathy (MMA) is a progressive intracranial occlusive arteriopathy that represents a leading cause of transient ischemic attacks and strokes in childhood. Despite this, up to now no large, exclusively pediatric MMA cohort has been subjected to systematic genetic investigation. In this study, we performed molecular karyotyping, exome sequencing and automated structural assessment of missense variants on a series of 88 pediatric MMA patients and correlated genetic, angiographic and clinical (stroke burden) findings. The two largest subgroups in our cohort consisted of RNF213 and neurofibromatosis type 1 (NF1) patients. While deleterious RNF213 variants were associated with a severe MMA clinical course with early symptom onset, frequent posterior cerebral artery involvement and higher stroke rates in multiple territories, NF1 patients had a similar infarct burden compared to non-NF1 individuals and were often diagnosed incidentally during routine MRIs. Additionally, we found that MMA-associated RNF213 variants have lower predicted functional impact compared to those associated with aortic disease. We also raise the question of MMA as a feature of recurrent as well as rare chromosomal imbalances and further support the possible association of MMA with STAT3 deficiency. In conclusion, we provide a comprehensive characterization at the genetic and clinical level of a large exclusively pediatric MMA population. Due to the clinical differences found across genetic subgroups, we propose genetic testing for risk stratification as part of the routine assessment of pediatric MMA patients.

Microdeletion 1p32p31 Presenting with Moyamoya Disease and Incomplete Hippocampal Inversion

“…Recently, a study of 88 pediatric MMA patients, which performed molecular karyotyping and exome sequencing, described deleterious variants mainly in the RNF213 and NF1 genes. Also, pathogenic copy number variants were found, including an Xq24 rearrangement, a 16p11.2 deletion together with a gain in 1q21.1-21.2, a 15q11.2 BP1-BP2 duplication, and a deletion in 1p36.22 [20]. Only a small deletion in one patient was found in the 1p31.3 region, including the AK4 gene.…”